title: Structure of an agonist-bound human A2A adenosine receptor.
abstract: Activation of G protein-coupled receptors upon agonist binding is a critical step in the signaling cascade for this family of cell surface proteins. We report the crystal structure of the A(2A) adenosine receptor (A(2A)AR) bound to an agonist UK-432097 at 2.7 angstrom resolution. Relative to inactive, antagonist-bound A(2A)AR, the agonist-bound structure displays an outward tilt and rotation of the cytoplasmic half of helix VI, a movement of helix V, and an axial shift of helix III, resembling the changes associated with the active-state opsin structure. Additionally, a seesaw movement of helix VII and a shift of extracellular loop 3 are likely specific to A(2A)AR and its ligand. The results define the molecule UK-432097 as a "conformationally selective agonist" capable of receptor stabilization in a specific active-state configuration.
authors.affiliation: Department of Molecular Biology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.forename: Huixian
authors.initials: H
authors.lastname: Wu
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Katritch
authors.forename: Gye Won
authors.initials: GW
authors.lastname: Han
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: Vadim
authors.initials: V
authors.lastname: Cherezov
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D058908:Adenosine A2 Receptor Agonists / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D055355:Opsins / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D043705:Receptor, Adenosine A2A / Q000737:chemistry* / Q000378:metabolism*; D012243:Rhodopsin / Q000737:chemistry / Q000378:metabolism; D014227:Triazines / Q000737:chemistry / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism
chemical_list: D058908:Adenosine A2 Receptor Agonists; D008024:Ligands; D055355:Opsins; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; C557757:UK-432097; C097270:ZM 241385; D012243:Rhodopsin; D000241:Adenosine